OBJECTIVE: This study was conducted to assess the dose proportionality, safety, and tolerability of fentanyl buccal tablet (FBT) in Japanese volunteers. METHODS: Healthy, opioid-naive Japanese adults received single-dose FBT 100, 200, 400, and 800 microg in a randomized, open-label, crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Peak serum fentanyl concentration (C(max)), time to C(max) (t(max)), area under the serum fentanyl concentration-time curve (AUC) from time 0 to infinity (AUC(0-infinity)), and AUC from 0 to the last quantifiable concentration (AUC(0-last)) were summarized using descriptive statistics. Dose proportionality was claimed if the ln-ln plots of C(max), AUC(0-infinity), and AUC(0-last) vs. dose were linear and the 90% confidence intervals (CI) of the slopes were within 0.8927 and 1.1073. The safety population comprised volunteers who received >/=1 FBT. RESULTS: Twenty-five volunteers were enrolled, 23 were included in the safety population (mean age 35.3 years), and 19 completed the study. The assessment of dose proportionality did not meet the statistical criteria (slope [90% CI]: 0.9118 [0.8601, 0.9635] for C(max), 1.0756 [1.0377, 1.1136] for AUC(0-infinity), and 1.0992 [1.0677, 1.1307] for AUC(0-last)). However, the increase in systemic exposure with dose appeared linear, and a post hoc analysis of partial AUCs from time 0 to 8, 12, 18, and 24 hours supported dose proportionality. Median t(max) of 90 minutes (range 30-180 minutes) was independent of dose. Adverse events (AEs) were mild or moderate. The most frequent AEs were nausea (N = 9), dizziness (N = 8), headache (N = 6), somnolence (N = 6), dyspepsia (N = 5), and vomiting (N = 3). No application-site or serious AEs were reported. CONCLUSIONS: Systemic exposure to FBT was approximately dose proportional across the range 100 microg to 800 microg in healthy Japanese adults. Adverse events were mild or moderate.